Oncotarget

Research Papers:

The generation and analyses of a novel combination of recombinant adenovirus vaccines targeting three tumor antigens as an immunotherapeutic

Elizabeth S. Gabitzsch, Kwong Yok Tsang, Claudia Palena, Justin David, Massimo Fantini, Anna Kwilas, Adrian E. Rice, Yvette Latchman, James W. Hodge, James L. Gulley, Ravi A. Madan, Christopher R. Heery, Joseph P. Balint Jr., Frank R. Jones and Jeffrey Schlom _

PDF  |  HTML  |  Supplementary Files  |  How to cite  |  Order a Reprint

Oncotarget. 2015; 6:31344-31359. https://doi.org/10.18632/oncotarget.5181

Metrics: PDF 1183 views  |   HTML 1531 views  |   ?  


Abstract

Elizabeth S. Gabitzsch1, Kwong Yok Tsang2, Claudia Palena2, Justin M. David2, Massimo Fantini2, Anna Kwilas2, Adrian E. Rice1, Yvette Latchman1, James W. Hodge2, James L. Gulley3, Ravi A. Madan3, Christopher R. Heery2, Joseph P. Balint Jr.1, Frank R. Jones1,*, Jeffrey Schlom2,*

1Etubics Corporation, Seattle, WA, USA

2Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

3Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

*These authors have contributed equally to this work

Correspondence to:

Jeffrey Schlom, e-mail: js141c@nih.gov

Keywords: cancer vaccines, adenovirus vaccines, tumor antigens, immunotherapy, brachyury

Received: June 18, 2015     Accepted: August 24, 2015     Published: September 07, 2015

ABSTRACT

Phenotypic heterogeneity of human carcinoma lesions, including heterogeneity in expression of tumor-associated antigens (TAAs), is a well-established phenomenon. Carcinoembryonic antigen (CEA), MUC1, and brachyury are diverse TAAs, each of which is expressed on a wide range of human tumors. We have previously reported on a novel adenovirus serotype 5 (Ad5) vector gene delivery platform (Ad5 [E1-, E2b-]) in which regions of the early 1 (E1), early 2 (E2b), and early 3 (E3) genes have been deleted. The unique deletions in this platform result in a dramatic decrease in late gene expression, leading to a marked reduction in host immune response to the vector. Ad5 [E1-, E2b-]-CEA vaccine (ETBX-011) has been employed in clinical studies as an active vaccine to induce immune responses to CEA in metastatic colorectal cancer patients. We report here the development of novel recombinant Ad5 [E1-, E2b-]-brachyury and-MUC1 vaccine constructs, each capable of activating antigen-specific human T cells in vitro and inducing antigen-specific CD4+ and CD8+ T cells in vaccinated mice. We also describe the use of a combination of the three vaccines (designated Tri-Ad5) of Ad5 [E1-, E2b-]-CEA, Ad5 [E1-, E2b-]-brachyury and Ad5 [E1-, E2b-]-MUC1, and demonstrate that there is minimal to no “antigenic competition” in in vitro studies of human dendritic cells, or in murine vaccination studies. The studies reported herein support the rationale for the application of Tri-Ad5 as a therapeutic modality to induce immune responses to a diverse range of human TAAs for potential clinical studies.


Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.
PII: 5181